Cancer Crosslinks 25 October 2017, Lund

Transcription

1 Cancer Crosslinks 25 October 2017, Lund Innovative Trial Design in an Era of Personalized Cancer Therapy Morten Mau-Sørensen, MD, PhD Phase 1 Unit, Rigshospitalet, Copenhagen

2 History 2

3 Precision Medicine Personalized Medicine tumor - targeted therapy host - pharmacogenomics 3

4 What is targeted therapy Target a defined process in cancer growth and/or development i.e hallmarks of cancer Target measurable or identifiable in tumors in patients Outcome of targeted therapy is correlated to the presence or absence of target Sledge, JCO editorial, p1614,

5 ~5 years Tamoxifen vs no tamoxifen in estrogen pos and neg disease ER-poor disease ER+ disease ER+ disease Targeted behandling Klinisk afprøvning af nye stoffer 5 Peto SABCS 2007

6 Should PARP inhibitors be considered taregeted therapy In BRCA pos/hrd pos ovarian cancer? Negative pts also derived benefit, although to a smaller extent Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer Mansoor R. Mirza et al NEJM 2016

7 Question: Does Personalized Therapy work? 7

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9 Answer:No Question: However, was the evaluated therapy truely targeted? (abiraterone, letrozole, tamoxifen, everolimus, sorafenib) Answer: No 9

10 Erlotinib in EGFR mut lung cancer Crizotinib in ALK pos lung cancer Vemurafenib in BRAFV600E mut malignant melanoma Trastuzumab cures HER2 pos early BC

11 Question: Does personalized therapy work? Answer1: Yes, in certain rare indications Answer2: Personalized therapy cures minimal disease HER2 pos early breast cancer Question: Does personalized therapy work in cancer in general: Answer: The jury is still out Challenge: How to evaluate personalized therapy in several very small entities with rare driver mutations 11

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13 Conventional trials based on histology Basket trials multiple histologies One driver mutation one drug Umbrella trials one histology Several driver mutation treated with one drug each

14 N-of-1 trials - Recruitment of patients exposed to different experimental agents or placebo in different sequencing, with washout periods in between - Each involved patient serves as his or her own comparator, through the comparison of the efficacy seen for the different experimental agents that the patient receives

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16 Tuxen et. al, APMIS 2014 RATIONALE DESIGN

17 Copenhagen Prospective Personalized Oncology (CoPPO) Primary Objectives: To obtain new biological knowledge To show that a genomic screening approach improves outcome Standard therapy Standard therapy Standard therapy No more standard therapy PFS 1 PFS 2 PFS 2 Relevant targeted therapy > 1.3 PFS 1 Tumor Progression Tumor Progression Tumor Progression Tumor Progression Secondary Objective: To enrich Phase 1 trials with appropriate patients To attract trials to the Phase 1 unit To accelerate drug development RATIONALE DESIGN OBJECTIVES

18 Copenhagen Prospective Personalized Oncology (CoPPO) Excluded (Not biopsible etc.) N = 88 Enrolled in CoPPO May Nov 2016 N = 500 Biopsy failure N = 50 (12%) Biopsied N = 412 Rebiopsy N = 23 Genomic profile N = 386 Not eligible for treatment N = 174 (47%) Eligible for treatment N = 212 Unmatched treatment N = 124 Treatment matched to profile N = 88 (23%) RATIONALE DESIGN OBJECTIVES METHODS RESULTS

19 Pros Genotype-driven clinical trials : Pros and cons - New and selective therapeutic options for patients - Better outcome Cons - Absence of agents in some detected driver targets - No direct clinical implication or benefit in a large proportion of screened patients - Difficulties to discriminate drivers from passengers targets

20 Future precision medicine: From sequencing to functionality in PDX and organoid models

21 More efforts is needed on : - Networking between institutions to render molecular tumor board accessible to the majority of centers and consequently to clinical trials and new drugs - More collaboration between pharmaceutical companies due to the need of drugs (including off label drugs) with the different mechanisms of action to be used in precision medicine -Role of liquid biopsy in determining the biological heterogeneity and evolution of the tumor

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23 Personalized therapy Conclusions Proof of Consept in tumors with rare drivers Personalized therapy can cure cancer (HER2+ early BC) Challenges Discern between driver and passager mutation Development of truely targeted therapies Evaluation of targeted therapy in histologically agnostic small entities driven by rare mutations Tumor heterogeniety remains a challenge 23

24 Why do pts on targeted therapy eventually fail Genetic Intratumor Heterogeneity Gerlinger M et al. N Engl J Med 2012;366:

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26 Acknowledgements Nurses and staff at the Phase I unit Research nursers at the Clinical Trials Unit And all the patients Dept. of Oncology: Ida Viller Tuxen - CoPP Ulrik Lassen - Founder of the phase I unit Morten Mau-Sørensen Kristoffer Rohrberg Iben Spanggaard Katrine Toubro Christoffer Johansen Dept. of Hematology Martin Hutchings Annette Vangsted Peter Brown Dept. of Genomic Medicine: Finn Cilius Nielsen Ane Yde Schmidt Christina Westmose Yde Olga Østrup Lise Barlebo Ahlborn Dept. of Clinical Genetics: Karin Wadt Dept. Of pathology: Jane Preuss Hasselby Eric Santoni-Rugiu BRIC: Bioinformatics Centre: Anders Krogh Janine Erler - PDX Organoids Institute Gustave Roussy, Paris Jean-Charles Soria Rosenfeld Group, Cancer Research, UK, Cambridge Institute Nitzan Rosenfeld Florent Mouliere Funding: Region Hovedstaden and Arvid Nilssons Foundation